Claims:We Claim:

1. A process for the preparation of Tedizolid (I), which comprising the steps of,

a) 5-bromo-2-(2-methyl-2H-tetrazol-5-yl) pyridine (XIII) is reacted with bis(pinacolato) diboron (XVI) in presence of dichlorobis(di-tert-butylphenylphosphine) palladium (II) / potassium acetate and organic solvent to get 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl) pyridine (XIV).

b) The product of step a) is reacted with (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxy methyl)-2-oxazolidin-2-one in presence of palladium catalyst / potassium acetate and organic solvent to get Tedizolid.

c) The product of step b) is reacted with phosphorylating agent in presence of organic base to get crude Tedizolid Phosphate, which is purified with DMSO to get pure Tedizolid Phosphate (I).

2. The process as claimed in claim 1, wherein the solvent is selected from group consisting of ethyl acetate, cyclohexane, dimethyl sulfoxide (DMSO), acetone, 1,4-dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, ethyl acetate, dichloromethane, acetic acid, methanol, ethanol, isopropanol and water;

3. The process as claimed in claim 1, wherein the phosphorylating agent is phosphorus oxychloride.

4. The process as claimed in claim 1, wherein the organic base is selected from triethylamine, diisopropylethylamine, pyridine, ethylamine and diisopropylamine. preferably triethylamine.

5. The process as claimed in claim 1, wherein the palladium catalyst is selected from group consisting of palladium (Pd) catalysts are selected from palladium (II) acetate, palladium (II) bromide, palladium (II) chloride, palladium (II) trifluoroacetate, bis(tricyclohexyl phosphine)palladium (II) chloride, tetrakis(triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium (II), dichlorobis(di-tert-butylphenyl phosphine)palladium (II), tetrakis(tri(o-tolyl)phosphine)palladium (0) and bis(dibenzyl ideneacetone)palladium (0).
, Description:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Tedizolid Phosphate. The present invention is also provides industrial applicable, commercially and eco-friendly viable process for the preparation of Tedizolid Phosphate.

BACKGROUND OF THE INVENTION

Tedizolid Phosphate of formula (I) or its phosphate salts are an oxazolidinone-class antibacterial drugs. Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria and it is commercially available in the market under the brand name SIVEXTRO ®. Tedizolid phosphate is chemically known as [(5R)-(3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl] phenyl}-2-oxo oxazolidin-5-yl] methyl hydrogen phosphate of formula (I).

(I)

US Patent US 7,816,379 of Dong-A pharm anticipates Tedizolid and pharmaceutically acceptable salts. US ‘379 also disclose a process for the preparation of Tedizolid phosphate, which describes the compound of formula (II) is reacted with benzyloxychloroformate in presence of THF / NaHCO3 to get the compound of formula (III). The compound of formula (III) is reacted with (R)-glycidyl butyrate in presence of THF / n-BuLi to get the compound of formula (IV). The compound of formula (IV) is reacted with iodide in presence of CH3CN / CF3COOAg to get the compound of formula (V). The compound of formula (V) is reacted with hexabutylditin in presence of 1,4-dioxane to get the compound of formula (VI). The compound of formula (VI) is reacted with the compound of formula (VII) to get Tedizolid. Tedizolid is reacted with di-tetrabutyldiisopropylphosphoamidite to get ditert-butyl ester of Tedizolid phosphate (VIII). The compound of formula (VIII) converts into Tedizolid Phosphate (I) in presence of MeONa / MeOH and CF3COOH.

The above process is schematically shown as below:

The main drawback of the above process, is the use of organo tin compounds such as hexabutylditin, one should take into consideration that they are highly toxic substances, whose quantitative separation is an essential prerequisite for the applicability of the product obtained and the discarding of which represents an important environmental issue.

The above prior-art process is, in terms of cost, relatively expensive reagents such as CF3COOAg are needed, and Pd catalyst are needed twice for respectively preparing intermediates in the process. The reaction conditions are not feasible for a large scale production.

WO 2010042887 of Trius Therapeutics., discloses process for the preparation of Tedizolid, which describes, the compound of formula (IX) is reacted with benzyloxychloroformate in presence of THF / NaHCO3 to get the compound of formula (X). The compound of formula (X) is reacted with B(Oi-Pr)3 in presence of THF / n-BuLi to get the compound of formula (XI). The compound of formula (XI) is reacted with the compound of formula (VII) in presence of Pd2(dba)3 / PCy3 and K2CO3 to get the compound of formula (XII). The compound of formula (XII) is reacted with (R)-glycidyl butyrate in presence of LiHMDS and THF to get Tedizolid, which is followed by reacted with POCl3 in presence of TEA to get Tedizolid Phosphate.

The above prior-art process, the reaction conditions are still intolerant Butyl lithium is needed, and the reaction needs to be carried out at ultra-low temperature. The use of n-BuLi and LiHMDS requires strict anhydrous condition.

The above prior-art process is not commercially and eco-friendly viable process. Hence, there is need for an improved and new process, which provides eco-friendly, better yield with more purity.

Therefore, the present invention is directed towards a novel, improved and cost effective process for the preparation of Tedizolid Phosphate (I) involves use of reagents that are less expensive, easier to handle and environmental friendly process without use of hazardous chemical reagents and / or provide a product of higher purity.

SUMMARY OF THE INVENTION

The present invention is to provide an improved, simple and cost-effective process for the preparation of Tedizolid phosphate with high purity and good yield on commercial scale.

In one aspect of the present invention provides a process for the preparation of Tedizolid Phosphate (I), which comprising the steps of,

a. 5-bromo-2-(2-methyl-2H-tetrazol-5-yl) pyridine (XIII) is reacted with bis(pinacolato) diboron (XVI) in presence of dichlorobis(di-tert-butylphenyl phosphine) palladium (II) / potassium acetate and organic solvent to get 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetra methyl-1,3, 2-dioxaboro lan-2-yl) pyridine (XIV).

b. The product of step a) is reacted with (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxy methyl)-2-oxazolidin-2-one in presence of palladium catalyst / potassium acetate and organic solvent to get Tedizolid.

c. The product of step b) is reacted with phosphorylating agent in presence of organic base to get crude Tedizolid Phosphate, which is purified with DMSO to get pure Tedizolid Phosphate (I).

In another aspect of the present invention provides a process for the preparation of the compound of formula (XIV) comprising, 5-bromo-2-(2-methyl-2H-tetrazol-5-yl) pyridine (XIII) is reacted with bis(pinacolato)diboron (XVI) in presence of dichlorobis(di-tert-butylphenylphosphine) palladium (II) / potassium acetate and organic solvent to get 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetra methyl-1,3, 2-dioxaboro lan-2-yl) pyridine (XIV).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved, simple and cost-effective process for the preparation of Tedizolid phosphate with high purity and good yield on commercial scale. The present invention is also provides industrial applicable, commercially and eco-friendly viable process for the preparation of Tedizolid Phosphate.

In an embodiment of the present invention provides a process for the preparation of Tedizolid Phosphate (I), which comprising the steps of,

a. 5-bromo-2-(2-methyl-2H-tetrazol-5-yl) pyridine (XIII) is reacted with bis(pinacolato) diboron (XVI) in presence of dichlorobis (di-tert-butylphenyl phosphine) palladium (II) / potassium acetate and organic solvent to get 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (XIV).

b. The product of step a) is reacted with (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxy methyl)-2-oxazolidin-2-one (Va) in presence of palladium catalyst / potassium acetate and organic solvent to get Tedizolid.

c. The product of step b) is reacted with phosphorylating agent in presence of organic base to get Tedizolid Phosphate, which is purified with DMSO to get pure Tedizolid Phosphate (I).

In an embodiment of the present invention, wherein reacting the compound 5-bromo-2-(2-methyl-2H-tetrazol-5-yl) pyridine (XIII) with bis(pinacolato)diboron (XVI) in presence of dichlorobis(di-tert-butylphenylphosphine) palladium (II) / potassium acetate and 1,4-dioxane, heated at 70-100ºC for 2-5 hrs preferably 80-85°C for 3-4 hrs to get 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl) pyridine (XIV). The compound of formula (XIV) is reacted with (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxy methyl)-2-oxazolidin-2-one (Va) in presence of palladium catalyst / potassium acetate and organic solvent to get Tedizolid, which is followed by reacted with phosphorus oxychloride in presence of TEA and THF, the reaction mixture was stirred at reflux for 10 mins to get crude Tedizolid Phosphate (I). Crude compound of Tedizolid phosphate is purified with dimethyl sulfoxide stir for 10 mins and heated to 50-70ºC for 1-4 hrs preferably 60-65°C for 1-2 hrs to get pure Tedizollid Phosphate (I).

In an embodiment of the present invention, suitable solvents that may be used in the process include, but are not limited to, alcohol solvents; ketone solvents; halogenated hydrocarbon solvents; ester solvents; nitrile solvents; polar aprotic solvents; water or mixtures thereof.

wherein the solvents are selected from group comprising of ethyl acetate, cyclohexane, dimethyl sulfoxide (DMSO), acetone, 1,4-dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, ethyl acetate, dichloromethane, acetic acid, methanol, ethanol, isopropanol and water;

In an embodiment of the present invention in step c) the phosphorylating agent is phosphorus oxychloride.
In an embodiment of the present invention, the bases are selected from triethylamine, diisopropylethylamine, pyridine, ethylamine and diisopropylamine; preferably triethylamine.

In an embodiment of the present invention, the palladium (Pd) catalysts are selected from palladium (II) acetate, palladium (II) bromide, palladium (II) chloride, palladium (II) trifluoro acetate, bis(tricyclohexylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine) palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichlorobis(di-tert-butylphenylphosphine)palladium (II), tetrakis(tri(o-tolyl)phosphine)palladium (0) and bis(dibenzylideneacetone)palladium (0).

In another embodiment of the present invention provides a process for the preparation of the compound of formula (XIV) comprising, 5-bromo-2-(2-methyl-2H-tetrazol-5-yl) pyridine (XIII) is reacted with bis(pinacolato)diboron (XVI) in presence of dichlorobis(di-tert-butylphenyl phosphine) palladium (II) / potassium acetate and organic solvent to get 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetra methyl-1,3, 2-dioxaboro lan-2-yl) pyridine (XIV).

In yet another embodiment, the present invention is a simple and operation friendly and industrial applicable process.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

Examples

Example-1:

Preparation of 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

100 gms of 5-bromo-2-(2-methyl-2H-tetrazole-5yl) pyridine, 122 gms of potassium acetate, 137.5 gms of bis(pinacolato)diboron and 2.0 gms of [dichlorobis(di-tert-butylphenylphosphine) palladium (II)] were taken in 1,4-dioxane (400 ml) at 25-30°C, heated to 80-85°C for 3-4 hrs. After completion of the reaction, solvent was removed under reduced pressure at below 50°C. Added water (500 ml) and extracted twice with dichloromethane (2×500 ml). The organic layers were combined and washed with water (300 ml), the resultant solvent was distilled out completely under reduced pressure, added cyclohexane (400 ml) to the reaction mixture and stir at 25-30°C for 2 hrs. The obtain solid was filtered and dried at 60-65°C for 12 hrs to get (110 gms) of 2-(2-methyl-2H-tetrazol-5-yl)-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxa borolan-2-yl) pyridine.

Yield: 90%

Purity: 99.8%.

Example-2:

Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-5-(hydroxy methyl) oxazolidin-2-one

100 gms of (R)-3-(-bromo-3-flourophenyl)-5-(hydroxy methyl) oxazolidine-2-one and 105 gms of 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl) pyridine are taken in 1,4-dioxane (500 ml)/ water (300 ml), added 102 gms of potassium acetate and 2 gms of [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium (II) and heated to 85-90°C for 15 hrs. After completion of the reaction, solvent is removed under reduced pressure; added water (500 ml) and dichloromethane (500 ml), then stir for 1-2 hrs. The precipitated solid was filtered and washed with dicloromethane (100 ml) and water (100 ml). The obtain wet cake was dried at 60-65°C for 12 hrs to get (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridine-3-yl) phenyl)-5-(hydroxy methyl) oxazolidin-2-one.
Yield: 85%

Purity: 97.5%.

Example-3:

Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl dihydrogen phosphate

100 gms of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-5-(hydroxy methyl) oxazolidin-2-one was taken in tetrahydrofuran (2000 ml), stir for 10 min and cool to 0-5ºC. 84 gms of triethylamine, 124.2 gms of phosphorous oxychloride solution diluted with tetrahydrofuran (100 ml) are added to reaction mixture at 0-5°C and stir for 3-4 hrs. The reaction mass was quench in ice water (2000 ml) at 0-10ºC and allow to heat at 20-25ºC. The resultant solid was filtered and dried at 60-65°C for 10-12 hrs to get (115 gr) crude material of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl dihydrogen phosphate.

Yield: 98%

Purity: 93%.

Example-4:

Purification of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl dihydrogen phosphate

100 gms of crude (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl dihydrogen phosphate is taken in dimethyl sulfoxide (250 ml) stir for 10 min and raise the temperature to 60-65°C, stir for 1-2 hrs, added acetonitrile (500 ml) at 60-65°C and allow to stir for 3-4 hrs. The precipitated solid was filtered and dried at 60-65°C for 10-12 hrs to get crude material of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxooxazolidine-5-yl) methyl dihydrogen phosphate.

Yield: 85%
Purity: 98.0%

Example-5:

Purification of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl dihydrogen phosphate

47 gms of sodium bicarbonate was taken in water (650 ml) stir for 10 min and slowly add 100 gms of above crude material (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl dihydrogen phosphate in portion wise and stir the reaction mass for 1-2 hrs. Adding 5.0 gms of charcoal to the reaction mass and stir for 30-45 min. filtered the reaction mass through hyflo bed and the filtrate is diluted with acetone (1000 ml).
Add (74 ml) of conc. hydrochloric acid to reaction mass and stir for 1-2 hrs at 0-5°C. The precipitated solid was filtered and dried at 60-65°C to get 80-90 gms pure material of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl dihydrogen phosphate.

Yield: 80%

Purity: 99.8%.